ProjectSummary Long-??chainpolyunsaturatedomega-??3fattyacids,suchasdocosahexaenoicacid(DHA)witha22-??carbon chain,arefoundabundantlyinoilyfishincludinganchovy,herring,mackerel,andsalmon.Theseomega-??3 fattyacidsarewidelythoughttohavemultiplehealth-??promotingeffects.EvidencesuggeststhatDHA decreasesbloodpressure,especiallyinhypertensivepatients.Wehypothesizethatthehypotensiveaction ofDHAismediatedbyitsstimulatoryeffectonlarge-??conductancecalciumandvoltage-??gatedpotassium (Slo1BK)channelsimportantinbloodpressureregulation.Theresearchprogramproposedherewill providemolecularandatomicbasisofthehypotensiveactionofDHAinvolvingSlo1BKchannelsusing biophysical,biochemical,andwhole-??animalmethods.Wepostulatethatahydrogenbondbetweena tyrosineresidueintheS6segmentofthechannelandthecarboxylategroupiscriticalindestabilizingthe closedconformationoftheionconductiongateandthisinteractionunderliesthewhole-??animal hypertensiveaction.Usingthephysicochemicalprincipleselucidated,wewillrationallydesign,synthesize andtestfatty-??acidactivatorsofSlo1BKchannels.Theanticipatedoutcomeoftheresearchprogramhas potentialtoexplainbloodpressureregulationofwholeanimalsbasedonthehydrogenbondsformed betweenspecifictyrosineresiduesoftheSlo1BKchannelandDHAandprovideasolidmechanistic foundationfordiscoveryanddevelopmentofpharmaceuticalsandnutraceuticalsforbloodpressure management.